Drug dependence is linked to decreased volume of limbic-related structures and to altered hippocampal morphology. Clinically, drug dependence is associated with limbic- and hippocampal-related symptoms, such as alterations in affect and emotion, and deficits in learning and memory. Clarification of the time course, extent, and cause of the changes in hippocampal structure and function will likely improve our understanding and treatment of addiction. One aspect of hippocampal plasticity potentially important for addiction research is the ability of the hippocampus to make new neurons throughout adulthood. Evidence suggests that the new hippocampal neurons are functionally integrated into hippocampal circuitry, and are involved in aspects of learning and memory. While much has been learned about what increases and decreases the number of new cells in the hippocampus, little progress has been made in identifying the cellular mechanisms underlying the regulation of adult hippocampus neurogenesis. This proposal is designed to explore how opiates regulate adult neurogenesis, and to explore the potential consequences of opiate-induced alterations in adult neurogenesis. There are three aspects to this proposal: a) We have shown that chronic, but not acute, opiate exposure inhibits the birth of new neurons in the adult hippocampus (Eisch et al., 2000). We will characterize the opiate-induced inhibition of adult neurogenesis by examining the time course of inhibition and alterations in the cell cycle. We also present data that a subset of newly born cells in the adult hippocampus express mu-opioid receptors. We will explore if mu-opioid receptor expression fluctuates across the cell cycle. b) We present data that certain cytokines and growth factors are decreased in the hippocampus after chronic morphine. To understand how morphine-induced changes in these factors alter adult neurogenesis, we will determine the time course of these changes relative to morphine exposure and explore if newly born hippocampal cells express receptors for these cytokines and growth factors. c) We present data that the morphine-induced decrease in adult hippocampal neurogenesis correlates with decreased hippocampal function. We will fully explore the deficit in hippocampal functioning caused by chronic morphine, particularly in relation to morphine-induced changes in adult neurogenesis and hippocampal levels of certain cytokines and growth factors. Examination of opiate-induced alterations of adult neurogenesis holds significant potential for testing the hypothesis that new neurons are important for learning and memory. In addition, comprehension of how opiates act to inhibit new neurons in the adult hippocampus will likely shed light on the basic mechanisms regulating neural stem cells. Importantly, such studies will improve our understanding of the complex mechanisms by which opiates affect brain function.